For quite some time, chemical compounds having immunomodulatory effects are known in the art. To these compounds also belongs 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt, the compound of the present invention, which is known for instance from the EP 1 203 587 A and has the following basic structure (Na+ not shown):

The above basic structure is also called luminol. It is known from prior art that 5-amino-2,3-dihydrophthalazine-1,4-dione alkali salts crystallize as solid matter in different hydrate forms. In prior art, in particular the dihydrate of the sodium salt (RU 2113222 C1) and a trihydrate of the potassium salt and mixed forms thereof (RU2211036 C2) are described.
It is known in the art that crystalline forms of a substance can differ in their physical properties such as solubility, dissolution rate, stability etc. (Haleblian and McCrone (1969): Journal of Pharmaceutical Sciences, 58:911-929).
Such properties can affect the pharmaceutical processing of the active ingredient as well as its biological availability and thus the biological efficacy (cf. Griesser (2006) in: Polymorphisms in the Pharmaceutical Industry. Hilfiker (Ed.) 211-234).
For the production of medicines, it is important that the original substance is stable, not water-drawing and controllable in its solid behavior during the complete production process. Further, the chemical stability and solid-phase stability with long storability of an active ingredient is extremely important (cf. Miller et al. (2006) in: Polymorphisms in the Pharmaceutical Industry. Hilfiker (Ed.) 385-403). It is desirable that even over a longer storing time, the physical properties of the active ingredient will be maintained. This relates, e.g., to the hygroscopicity, solubility or initial dissolution rate of the active ingredient.
U.S. Pat. No. 6,489,326 B1 describes a method for producing a 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt to be used for medical purposes, which results in a dihydrate form. The drawback of this method is the use of a heavy-metal catalyst that may leave residues in the product. Products with residues have allergenic potential and in general are deemed critical for pharmaceutical use by the EMEA (cf. Guideline EMEA/CHMP/SWP/4446/2000).
Very important for the pharmaceutical processing and the medical use are production methods, which reliably and reproducibly permit the production of the desired crystalline forms. When producing crystalline forms, it should be considered that small deviations of the process parameters will already cause changes of the crystal structure of the products and can thus finally lead to different crystalline forms or mixed forms. Properties changed thereby—for instance a modified biological efficacy by a different solubility—may lead to a rejection of complete batches, often it is not possible at all to produce the desired form (cf. Ulrich and Jones (2005): Nachrichten aus der Chemie 53:19-23). Besides the degree of purity of the active ingredient and the resulting possible changes of the efficacy, further important properties for the pharmaceutical processing can be affected in an adverse manner, e.g. the capability to be pressed to tablets by an impairment of the pourability or flow rate of the crystalline form. 5-Amino-2,3-dihydrophthalazine-1,4-dione alkali salts belong to the group of the aminophthalhydrazides and are described in prior art as immunomodulators with special antiinflammatory, antioxidative and antitoxic properties (cf. U.S. Pat. No. 6,489,326 B1; EP 0617024, U.S. Pat. No. 5,512,573, U.S. Pat. No. 5,543,410 A, U.S. Pat. No. 7,326,690 B2).
Immunomodulatory substances are commonly grouped according to their effects into immunodepressants and immunostimulants (cf. Rote Liste Service GmbH (2011): www.rote-liste.de).
The corresponding preparations having exclusively immunodepressive or exclusively immunostimulating effect, such as for instance immunodepressive TNF alpha-blockers or immunostimulating interferon beta-preparations, often cause significant undesired side effects in the organism, exactly because of their very specific mechanism of action. Some known immunodepressive substances, such as for instance the TNF alpha-blocker adalimumab, specifically inhibit certain inflammatory mediators. Such therapies are known to have serious side effects (cf. Descotes (2008): Expert Opin. Drug Metab. Toxicol., 4: 12: 1537-1549), since the blocking of individual inflammatory mediators is a severe intervention of the complex immune system. Consequently, the organism is not capable anymore to fulfill its functions, to react automatically and physiologically appropriately to exogenous or endogenous inflammatory stimuli, such as e.g. bacterial infections. Thus, for instance, the application of TNF alpha-blockers is contraindicated in the case of serious infections, this applies in particular for sepsis and tuberculosis. Before administering a corresponding medication, such as e.g. for the treatment of rheumatoid arthritis, a TBC screening is strongly recommended (cf. Diel et al. (2009): Z Rheumatol 5:411-416). Moreover, Hoffmann (2005: Intensivmed 42:371-377) could clearly demonstrate that TNF alpha-blockers are not suitable for the clinical application in case of septic conditions, but to the contrary can even lead to an increase of mortality.
The particular immunomodulatory properties of the 5-amino-2,3-dihydrophthalazine-1,4-dione alkali salts are however distinctly useful for the prevention of so-called cytokine storms (cf. Suntharalingam et al. (2006): N Engl J Med 355; 1018-28) caused by excessive immune responses. Different from so-called cytokine blockers, these salts are mostly free from side effects, since an inhibition of individual cytokines will not take place, but these are regulated to a physiological level, and thus an adequate reaction of the organism to infectious germs is assured further on. However, prior art does not allocate any different immunospecific effects to individual crystalline forms of alkali salts for 5-amino-2,3-dihydrophthalazine-1,4-dione. In particular, no statements can be found in prior art, whether individual crystalline forms can be used specifically and according to indication, i.e. according to their basic, specific immunomodulatory main effect, preferably as immunodepressants or preferably as immunostimulants.
A special medical application of the 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt is described in the US 2003/0195183 A1 with the “Correction of the immune system” by using different doses (0.2 μg to 1,000 mg) of 5-amino-2,3-dihydrophthalazine-1,4-dione alkali salts in different experimental runs. Effective doses within this range varied depending on the examined disease and individual parameters such as e.g. species, age, gender, and weight. For instance, the application of different doses between 2 and 200 μg of 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt will lead to different consequences for the cellular immune response of mice induced by subcutaneous injection of erythrocytes (delayed hypersensitivity response—DHR). The lower is the used dose, the higher is the DHR index. In the more sensitive one of the two used mice strains, the highest dose will lead to an inhibition of the DHR. This example and further in vivo, in vitro and also clinical examples in the US 2003/0195183 A1 indicate that low doses of 5-amino-2,3-dihydrophthalazine-1,4-dione alkali salts mainly act in an immunostimulating manner, whereas higher doses of 5-amino-2,3-dihydrophthalazine-1,4-dione alkali salts mainly act in an immunodepressive manner. Since the transition from immunostimulating dose to immunodepressive dose for different mice strains is differently high, the treatment of different species and individuals in the human and veterinary medicine will also cause population-genetic effects, whereby particular risks of this dose-dependent application will result.
Therefore, for the clinical practice, in particular for the prevention of severe diseases with congenital or acquired immune deficiency or with excessive immune responses, a method for specifically controlling the immunomodulation by the simple provision of different polymorphs of a substance would be advantageous.
The property of a preferably stimulating immunomodulator is desirable for instance for the therapeutic treatment of patients having a weak immune defense, such as after an HIV infection or after a chemotherapeutic treatment.
The property of a preferably depressive immunomodulator is desirable, for instance for minimizing inflammatory processes, such as in case of a surgical operation, autoimmune diseases and allergies.
In the clinical practice, for some indications, in particular relapsing inflammatory diseases, immunostimulants as well as immunodepressants are often therapeutically used simultaneously or alternatingly (cf. DMSG 2006: Aktuelle Therapieempfehlungen September 2006; Rote Liste Service GmbH (2011): www.rote-liste.de). This will lead to an increased risk of interactions. Chemically similar substances of a substance class that are capable to produce opposite effects, would therefore offer an advantage for the clinical practice, since it can be expected that they will cause, with simultaneous or time-displaced administration, less pharmacologically caused interactions in the organism than active ingredients of different substance classes used for the same purposes.
A drawback of the prior art is further that a dose-dependent application of an immunomodulator requires higher attentiveness of the administering medical staff or of the patients themselves and thus increases the risk of application errors.
Therefore a not only dose-dependent immunospecific application of a 5-amino-2,3-dihydrophthalazine-1,4-dione alkali salt is desirable for a practical and low-risk therapeutic application, which in addition exploits the medical advantages of this substance class.
It needs to be noted that interventions in the complex rules of the immune system may have serious consequences for the involved organism. The more important for the medical application are therefore immunomodulators having as few side effects as possible and an immunologically defined effect, which makes a specific prophylaxis or therapy of immunologically caused diseases possible. Such immunomodulators would have a great importance for the medicine.